PROJECT SUMMARY Asprosin, a newly identified glucogenic hormone through study of neonatal progeroid syndrome (NPS, or Marfan lipodystrophy syndrome), may have both therapeutic and diagnostic implications for obesity and diabetes. The gene encoding asprosin, FBN1, has unique extreme 3? mutations resulting in hypoglycemic symptoms and low plasma insulin levels in a few patients with the rare NPS. Considerable evidence has recently demonstrated asprosin?s direct role in hepatic glucose production modulation, and asprosin immunologic neutralization in the treatment of obesity and diabetes in mouse models. The direct effect of asprosin on type 2 diabetes (T2D) incidence in humans has not been investigated in human populations. The current application aims to investigate the potential causal role of asprosin for obesity and T2D development in two large and high-quality prospective cohorts of men and women. We plan to integrate data on relevant genetic variations, biochemical markers, and clinical phenotypes of obesity and T2D incidence in the national Women?s Health Initiative (WHI) and the men?s Health Professionals Follow-Up Study (HPFS). Both WHI and HPFS are long-term prospective cohorts that have been funded by the NIH with detailed and high-quality dietary, lifestyle, clinical, biochemical, and genomic data, and a large number of well-characterized and validated incident T2D cases using standardized protocol consistently over 20 years of follow-up. All incident T2D cases with existing genetic data and fasting blood samples (n1=2,615) matched by an equal number of controls (n0=2,615) randomly selected from the same WHI cohort of women, and 600 case-control pairs of men (n?=1,200) will be included using the identical nested case- control design. Genotyping and validation analyses will be performed in an additional 1,076 T2D case-control pairs (n?=2,152) without existing genetic data. Adopting both standard statistical methods and the cutting-edge Mendelian randomization method for causal inference, we will leverage these exceptional resources and the substantial investment of time and effort by WHI/HPFS study investigators over the past two decades to investigate, in a most cost-efficient and timely manner, the effect of this novel and promising hormone ? asprosin ? for obesity and T2D development. We will be the first to investigate 1) the distribution of plasma asprosin levels in men and women, 2) the genetic variations affecting asprosin functions in diverse human populations, and 3) the potential causal relation between asprosin and obesity and T2D in human populations of diverse ethnicity including white or Caucasian American (CA), African American (AA), and Hispanic American (HA).